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Observation has frequently been the foundation for some of the most important research in medicine. New findings based on properly designed studies with well-established statistical methods can influence patient care. When an observational study reports a new finding from a properly designed trial, there are at least 3 fundamental questions that should be asked to assess its significance: 1) What is its mechanism? 2) What is the relationship to the end point (i.e., cause and effect or just an association)? 3) Are the findings relevant?

In some situations, the answers are rather obvious. For example, thrombolytic therapy or primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) can open occluded coronary arteries, limit infarct size, and significantly decrease mortality (1). In other instances, the answers can be less apparent. Patients with an elevated C-reactive protein in most studies are at increased risk for adverse events on follow-up independent of conventional risk. Is this an association (i.e., a marker of inflammation or of atherosclerotic burden) or could there be a casual relationship secondary to a direct effect of the molecule (2)?

In this issue of JACC: Cardiovascular Interventions, Valgimigli et al. (3) report on a pooled analysis from 2 glycoprotein inhibitor trials comparing tirofiban to abciximab for primary PCI in STEMI. The second, and larger of the 2 trials, the MULTISTRATEGY (Multicenter Evaluation of single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study), also had a second randomization comparing drug-eluting to bare-metal stenting (4). Persistent TIMI (Thrombolysis In Myocardial Infarction) flow grade 0 after wire insertion (AWI) was found to be a predictor of 30-day and 1-year mortality in patients who otherwise had a successful primary PCI (3). In a multivariate analysis correcting for several potential confounders, there was a 2- to 3-fold increase in mortality associated with persistent TIMI flow grade 0 AWI (an absolute 3.8% to 5.8% increase in mortality) despite 89% achieving TIMI flow grade 3 following PCI (an independent core laboratory adjudicated all angiograms). TIMI flow grade 0 AWI was a common phenomenon present in 266 (49%) of the 540 individuals who presented with baseline TIMI flow grade 0. The majority but not all of these patients were treated appropriately at discharge with class I medications.

In an attempt to determine the significance of this finding of persistent TIMI flow grade 0 AWI, the first question that comes to mind is why does an occluded coronary artery following acute STEMI open after wire manipulation? A likely answer would be that in these cases, the thrombus burden is not that large and wire manipulation causes a small amount of thrombus to dislodge, embolize distally, and allow for some antegrade flow distally. Fresh thrombus is friable and is platelet-fibrin rich. Acutely, it may not be firmly attached to the vessel wall substrate (5). Alternatively, the wire may puncture a hole and merely create a channel within a more organized thrombus without necessarily leading to distal embolization. Studies of PCI using distal protection, however, commonly find plaque or thrombus in the filter device (6,7). In the EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) and PROMISE (Protection Devices in PCI-Treatment of Myocardial Infarction for Salvage of Endangered Myocardium Study) trials of distal protection in STEMI, roughly 30% to 70% of patients had either plaque and/or thrombus debris retrieved in the filter device (6,7). Temporally, the timing of embolization (wire placement and/or balloon stent inflation) cannot be ascertained in these studies given the fact that the protection device was only removed after the procedure was finished. However, it has been shown that slow distal flow is most likely to occur during balloon/stent deployment particularly if the balloon/artery ratio is >1.0 (8,9). In addition, creatine kinase release following PCI in saphenous vein grafts is more likely to occur when the stent/artery (vein graft) ratio is >1.2 (10). One may also consider that the wire relieves vasospasm as another potential mechanism for partial distal flow although anecdotally, this appears unlikely as the reverse is usually the case. Vasospasm is a common phenomenon caused by wire manipulation.

Concerning the 3 questions initially proposed the last is easiest to answer in this study. A novel finding that identifies those at higher risk of mortality after primary PCI for STEMI is potentially very relevant particularly if there are maneuvers that might reverse the adverse outcome. The other questions are not as easy to resolve. If the mechanism of TIMI flow grade 0 AWI is a larger thrombus burden that prevents the vessel from opening following wire placement, then embolization during balloon or stent inflation could be a likely scenario leading to larger infarctions that increase cardiovascular mortality. Here, there could be a cause/effect relationship of TIMI flow grade 0 AWI to increased mortality. The fact that patients with persistent TIMI flow grade 0 AWI in comparison with those without persistent TIMI flow grade 0 had significantly less ST-segment resolution, lower left ventricular ejection fractions at discharge, as well as a lower incidence of TIMI flow grade 3 after the procedure could support this hypothesis. Furthermore, if indeed this was the mechanism, then targeting this group with specific therapeutic maneuvers before stent deployment could potentially improve outcomes. Routine thrombectomy, distal protection, and possibly even a local intracoronary infusion of small doses of a thrombolytic therapy might be considered approaches that could be prospectively evaluated in randomized trials.

By contrast, the increased mortality and less ST-segment resolution and so forth seen with persistent TIMI flow grade 0 AWI could be a consequence of the later time to reperfusion (a median of 40 min in this group) in comparison with those with baseline TIMI flow grade than reopened AWI. The later the time to reperfusion, the more likely that the thrombus will be organized and/or there will be greater microvascular damage (11). In this case, the finding of persistent TIMI flow grade 0, which in this study, was more likely to be the case in patients whose symptoms began at least 3 h before PCI, would be more of an association rather than responsible for the end point and a therapeutic trial targeting thrombus, as mentioned, may not be as effective (3). A combination of both processes (larger thrombus burden and later reperfusion) could be responsible in other cases.

Whether or not this study satisfies the 3 questions initially proposed, this finding was derived retrospectively and as such is more hypothesis-generating. Procedural variables other than the use of primary stenting and post-stenting dilation are lacking. The adequacy of stent deployment and the type of stent (bare-metal vs. drug-eluting), differences in anticoagulant regimens, use of intracoronary vasodilators, how and when thrombectomy was used, and who received post-discharge medicines and at what dose are just a few of the potential cofounders that could be responsible for the worse outcome in those with persistent TIMI flow grade 0 AWI. Even the type of wire (hydrophilic or uncoated) might also have played a role in whether thrombus embolized downstream or whether just a channel within the thrombus was created leading to TIMI flow grade 0 AWI.

Based on the deficiencies of this analysis, is it then reasonable to pursue further study? Given the potential benefits of reducing mortality, we think the answer is yes. Future trials that are appropriately sized should consider these and other potential confounders. Several end points including noninvasive determinants of infarct size, myocardial blush scores, ST-segment resolution as well as cardiovascular (3) mortality should be assessed and different therapeutic maneuvers including routine thrombectomy and distal protection and so forth should be tested prospectively. Despite the limitations in this study, the investigators should be congratulated on their analysis. Their provocative and potentially important findings should generate further study that may ultimately improve patient care.

Footnotes

The authors have reported that they have no relationships to disclose.

↵⁎ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.

American College of Cardiology Foundation

References

(1994) Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet343:311–322.

(2008) Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial. JAMA299:1788–1799.

(2005) Randomized evaluation of the effects of filter-based distal protection on myocardial perfusion and infarct size after primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation. Circulation112:1462–1469.